Infection by HIV and progression to AIDS involves a complex interaction between the host's immune system, HIV, and a variety of cofactors. Amongst these cofactors, epidemiological evidence supports a role for "crack" cocaine as an independent risk factor for the development of HIV and AIDS. Corroborating these findings, we have shown that exposure to cocaine enhances viral infection, increases systemic viral load, and the loss of CD4+ cells in vivo in immudeficient mice engrafted wtih human peripheral blood leucocytes. Understanding how cocaine mediates these effects is the major focus of this proposal. As we have recently shown that antigen (Ag) presentation by dendritic cells (DC) leads to the upregulation of CD4 and chemokine coreceptors on responder T cells and enhances their susceptibility to infection by HIV, we have hypothesized that cocaine modulates this process, producing a unique interaction/synergy that increases susceptibility to, and, replication of HIV. To test this hypothesis, we propose the following specific aims: Aim 1: To investigate how acute exposure to cocaine during an Ag-challenge promotes HIV infection of T cells in vivo in the huPBL-NOD-SCID/IL2rg-null model. Aim 2: To determine the effects of habitual exposure to cocaine on viral pathogenesis and immune responsiveness in a NOD-SCID/IL2rg-null mouse/human hybrid model of chronic HIV infection. Short-term studies in the huPBL-NOD-SCID/IL2rg-null model proposed for Aim 1 will focus on an infectious Ag challenge as a cofactor for increasing HIV infection and the mechanisms by which cocaine enhances HIV infection of the resulting Ag-specific CD4+ and CD8+ T cells. In addition, these studies will provide important insight into the capacity for an HIV-compromised immune system to mount effective vaccine responses. Finally, as proposed for Aim 2, the development and testing of stable mouse-human chimeras that exhibit functional immune systems will be used to extend our observations into a model of chronic HIV infection and habitual cocaine abuse, providing one of the most flexible and relevant animal models in which to study the in vivo effects of habitual drug abuse on human immunity and HIV infection.